Biliary atresia (BA) is the most common cause of pediatric end-stage liver disease in the U.S. However, there is no effective treatment for BA due to a lack of human cellular model of the disease that would facilitate mechanistic studies or development of potential drugs and prevention strategies. In order to overcome this hurdle, we have successfully generated multiple patient-specific induced pluripotent stem cell (iPSC) lines from BA patients. We have also created a panel of isogenic human iPSC lines with precise genome editing at reported BA susceptibility loci. Based on these BA-relevant human iPSC lines and our expertise on recapitulating early human hepatic and biliary organ development from iPSCs, we propose to develop the first disease-relevant human model for understanding molecular basis of early BA development. Our preliminary results have indicated an altered biliary differentiation in the BA-iPSC lines. This study aims at further validating the disease model by characterizing the functional defects in hepatobiliary differentiation stages. We also aim to identify key pathways responsible for BA development by RNA-Seq analyses. Completion of this study will significantly enhance our understanding of human biliary system development. The BA model developed in this study will provide a powerful tool and a novel assay platform to study the genetic basis of developmental defects in BA, to understand the interactions between genetic and environmental risk factors and to develop potential drug treatments.

Public Health Relevance

This study aims to establish a disease-relevant human cellular model of Biliary Atresia that recapitulates the abnormal early hepatobiliary development. The disease model developed in this study will provide a powerful tool and a novel assay platform to study the genetic basis of developmental defects in Biliary Atresia, to understand the interactions between genetic and environmental risk factors and to develop potential drug treatments.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
1R03HD091264-01A1
Application #
9598384
Study Section
National Institute of Child Health and Human Development Initial Review Group (CHHD)
Program Officer
Toyama, Reiko
Project Start
2018-07-20
Project End
2020-06-30
Budget Start
2018-07-20
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Tian, Lipeng; Ye, Zhaohui; Kafka, Kim et al. (2018) Biliary Atresia Relevant Human iPSCs Recapitulate Key Disease Features in a Dish. J Pediatr Gastroenterol Nutr :